4.1. Therapeutic indications

Deferasirox Mylan is indicated for the treatment of chronic iron overload due to frequent blood transfusions (≥7 ml/kg/month of packed red blood cells) in patients with beta thalassaemia major aged 6 years and older.

Deferasirox Mylan is also indicated for the treatment of chronic iron overload due to blood transfusions when deferoxamine therapy is contraindicated or inadequate in the following patient groups:

– in paediatric patients with beta thalassaemia major with iron overload due to frequent blood transfusions (≥7 ml/kg/month of packed red blood cells) aged 2 to 5 years,

– in adult and paediatric patients with beta thalassaemia major with iron overload due to infrequent blood transfusions (<7 ml/kg/month of packed red blood cells) aged 2 years and older,

– in adult and paediatric patients with other anaemias aged 2 years and older.

Deferasirox Mylan is also indicated for the treatment of chronic iron overload requiring chelation therapy when deferoxamine therapy is contraindicated or inadequate in patients with non-transfusion-dependent thalassaemia syndromes aged 10 years and older.

4.2. Posology and method of administration

All references to the dispersible tablet formulation throughout the SmPC refer to medicinal products by different Marketing Authorisation Holders with dispersible tablet formulations of the active ingredient deferasirox.

Treatment with Deferasirox Mylan should be initiated and maintained by physicians experienced in the treatment of chronic iron overload.

Posology

Transfusional iron overload

It is recommended that treatment be started after the transfusion of approximately 20 units (about 100 ml/kg) of packed red blood cells (PRBC) or when there is evidence from clinical monitoring that chronic iron overload is present (e.g. serum ferritin >1,000 µg/l). Doses (in mg/kg) must be calculated and rounded to the nearest whole tablet size.

The goals of iron chelation therapy are to remove the amount of iron administered in transfusions and, as required, to reduce the existing iron burden.

Caution should be taken during chelation therapy to minimise the risk of over-chelation in all patients (see section 4.4).

The recommended doses are shown in the table below.

In the EU, medicines containing deferasirox are available as film-coated tablets and dispersible tablets marketed under different tradenames as generic alternatives of deferasirox. Due to different pharmacokinetic profiles, a 30% lower dose of deferasirox film-coated tablets is needed in comparison to the recommended dose for deferasirox dispersible tablets (see section 5.1).

Table 1 Recommended doses for transfusional iron overload

Film-coated tablets

Transfusions

Serum ferritin

Starting dose

14 mg/kg/day

After 20 units (about 100 ml/kg) of PRBC

or

>1,000µg/l

Alternative starting doses

21 mg/kg/day

>14 ml/kg/month of PRBC (approx. >4 units/month for an adult)

7 mg/kg/day

<7 ml/kg/month of PRBC (approx. <2 units/month for an adult)

For patients well managed on deferoxamine

One third of deferoxamine dose

Monitoring

Monthly

Target range

500 – 1,000 µg/l

Adjustment Steps

(every 3 – 6 months)

Increase

3.5 – 7 mg/kg/day

>2,500 µg/l

Up to 28 mg/kg/day

Decrease

3.5 – 7 mg/kg/day

<2,500 µg/l

In patients treated with doses >21 mg/kg/day

When target is reached

500 – 1,000 µg/l

Maximum dose

28 mg/kg/day

Consider interruption

<500 µg/l

Starting dose

The recommended initial daily dose of Deferasirox Mylan film-coated tablets is 14 mg/kg body weight.

An initial daily dose of 21 mg/kg may be considered for patients who require reduction of elevated body iron levels and who are also receiving more than 14 ml/kg/month of packed red blood cells (approximately >4 units/month for an adult).

An initial daily dose of 7 mg/kg may be considered for patients who do not require reduction of body iron levels and who are also receiving less than 7 ml/kg/month of packed red blood cells (approximately <2 units/month for an adult). The patient's response must be monitored and a dose increase should be considered if sufficient efficacy is not obtained (see section 5.1).

For patients, already well managed on treatment with deferoxamine, a starting dose of Deferasirox Mylan film-coated tablets that is numerically one third that of the deferoxamine dose could be considered (e.g. a patient receiving 40 mg/kg/day of deferoxamine for 5 days per week (or equivalent) could be transferred to a starting daily dose of 14 mg/kg/day of Deferasirox Mylan film-coated tablets). When this results in a daily dose less than 14 mg/kg body weight, the patient's response must be monitored and a dose increase should be considered if sufficient efficacy is not obtained (see section 5.1).

Dose adjustment

It is recommended that serum ferritin be monitored every month and that the dose of Deferasirox be adjusted, if necessary, every 3 to 6 months based on the trends in serum ferritin. Dose adjustments may be made in steps of 3.5 to 7 mg/kg and are to be tailored to the individual patient's response and therapeutic goals (maintenance or reduction of iron burden). In patients not adequately controlled with doses of 21 mg/kg (e.g. serum ferritin levels persistently above 2,500 µg/l and not showing a decreasing trend over time), doses of up to 28 mg/kg may be considered. The availability of long-term efficacy and safety data from clinical studies conducted with deferasirox dispersible tablets used at doses above 30 mg/kg is currently limited (264 patients followed for an average of 1 year after dose escalation). If only very poor haemosiderosis control is achieved at doses up to 21 mg/kg (film-coated tablet dose equivalent of 30mg/kg of dispersible tablets), a further increase (to a maximum of 28 mg/kg) may not achieve satisfactory control, and alternative treatment options may be considered. If no satisfactory control is achieved at doses above 21 mg/kg, treatment at such doses should not be maintained and alternative treatment options should be considered whenever possible. Doses above 28 mg/kg are not recommended because there is only limited experience with doses above this level (see section 5.1).

In patients treated with doses greater than 21 mg/kg, dose reductions in steps of 3.5 to 7 mg/kg should be considered when control has been achieved (e.g. serum ferritin levels persistently ≤2,500 µg/l and showing a decreasing trend over time). In patients whose serum ferritin level has reached the target (usually between 500 and 1,000 µg/l), dose reductions in steps of 3.5 to 7 mg/kg should be considered to maintain serum ferritin levels within the target range and to minimise the risk of over-chelation. If serum ferritin falls consistently below 500 µg/l, an interruption of treatment should be considered (see section 4.4).

Non-transfusion-dependent thalassaemia syndromes

Chelation therapy should only be initiated when there is evidence of iron overload (liver iron concentration [LIC] ≥5 mg Fe/g dry weight [dw] or serum ferritin consistently >800 µg/l). LIC is the preferred method of iron overload determination and should be used wherever available. Caution should be taken during chelation therapy to minimise the risk of over-chelation in all patients (see section 4.4).

The recommended doses are shown in the table below.

In the EU, medicines containing deferasirox are available as film-coated tablets and dispersible tablets marketed under different tradenames as generic alternatives of deferasirox. Due to different pharmacokinetic profiles, a 30% lower dose of deferasirox film-coated tablets is needed in comparison to the recommended dose for deferasirox dispersible tablets (see section 5.1).

Table 2 Recommended doses for non-transfusion-dependent thalassaemia syndromes

Film-coated tablets

Liver iron concentration (LIC)*

Serum ferritin

Starting dose

7 mg/kg/day

≥5 mg Fe/g dw

or

>800 µg/l

Monitoring

Monthly

Adjustment steps

(every 3 – 6 months)

Increase

3.5 – 7 mg/kg/day

≥7 mg Fe/g dw

or

>2,000 µg/l

Decrease

3.5 – 7 mg/kg/day

<7 mg Fe/g dw

or

≥2,000 µg/l

Maximum dose

14 mg/kg/day

For adult patients

7 mg/kg/day

For Paediatric patients

7mg/kg/day

For both adults and paediatric patients

not assessed

and

≤2,000 µg/l

Interruption

<3 mg Fe/g dw

or

<300 µg/l

Retreatment

Not recommended

* LIC is the preferred method of iron overload determination.

Starting dose

The recommended initial daily dose of Deferasirox Mylan film-coated tablets in patients with non-transfusion-dependent thalassaemia syndromes is 7 mg/kg body weight.

Dose adjustment

It is recommended that serum ferritin be monitored every month to assess the patient's response to therapy and to minimise the risk of over-chelation (see section 4.4). After every 3 to 6 months of treatment, a dose increase in increments of 3.5 to 7 mg/kg should be considered if the patient's LIC is ≥7 mg Fe/g dw, or if serum ferritin is consistently >2,000 µg/l and not showing a downward trend, and the patient is tolerating the medicinal product well. Doses above 14 mg/kg are not recommended because there is no experience with doses above this level in patients with non-transfusion-dependent thalassaemia syndromes.

In both paediatric and adult patients in whom LIC was not assessed and serum ferritin is ≤2,000 µg/l, dosing should not exceed 7 mg/kg.

For patients in whom the dose was increased to >7 mg/kg, dose reduction to 7 mg/kg or less is recommended when LIC is <7 mg Fe/g dw or serum ferritin is ≤2,000 µg/l.

Treatment cessation

Once a satisfactory body iron level has been achieved (LIC <3 mg Fe/g dw or serum ferritin <300 µg/l), treatment should be stopped. There are no data available on the retreatment of patients who reaccumulate iron after having achieved a satisfactory body iron level and therefore retreatment cannot be recommended.

Special populations

Elderly patients (≥65 years of age)

The dosing recommendations for elderly patients are the same as described above. In clinical studies, elderly patients experienced a higher frequency of adverse reactions than younger patients (in particular, diarrhoea) and should be monitored closely for adverse reactions that may require a dose adjustment.

Paediatric population

Transfusional iron overload:

The dosing recommendations for paediatric patients aged 2 to 17 years with transfusional iron overload are the same as for adult patients (see section 4.2). It is recommended that serum ferritin be monitored every month to assess the patient's response to therapy and to minimise the risk of over-chelation (see section 4.4). Changes in weight of paediatric patients over time must be taken into account when calculating the dose.

In children with transfusional iron overload aged between 2 and 5 years, exposure is lower than in adults (see section 5.2). This age group may therefore require higher doses than are necessary in adults. However, the initial dose should be the same as in adults, followed by individual titration.

Non-transfusion-dependent thalassaemia syndromes:

In paediatric patients with non-transfusion-dependent thalassaemia syndromes, dosing should not exceed 7 mg/kg. In these patients, closer monitoring of LIC and serum ferritin is essential to avoid over-chelation (see section 4.4). In addition to monthly serum ferritin assessments, LIC should be monitored every three months when serum ferritin is ≤800 µg/l.

Children from birth to 23 months:

The safety and efficacy of Deferasirox Mylan in children from birth to 23 months of age have not been established. No data are available.

Patients with renal impairment

Deferasirox Mylan has not been studied in patients with renal impairment and is contraindicated in patients with estimated creatinine clearance <60 ml/min (see sections 4.3 and 4.4).

Patients with hepatic impairment

Deferasirox Mylan is not recommended in patients with severe hepatic impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the dose should be considerably reduced followed by progressive increase up to a limit of 50% of recommended treatment dose for patients with normal hepatic function (see sections 4.4 and 5.2), and Deferasirox Mylan must be used with caution in such patients. Hepatic function in all patients should be monitored before treatment, every 2 weeks during the first month and then every month (see section 4.4).

Method of administration

For oral use.

The film-coated tablets should be swallowed whole with some water. For patients who are unable to swallow whole tablets, the film-coated tablets may be crushed and administered by sprinkling the full dose onto soft food, e.g. yogurt or apple sauce (pureed apple). The dose should be immediately and completely consumed, and not stored for future use.

The film-coated tablets should be taken once a day, preferably at the same time each day, and may be taken on an empty stomach or with a light meal (see sections 4.5 and 5.2).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Combination with other iron chelator therapies as the safety of such combinations has not been established (see section 4.5).

Patients with estimated creatinine clearance <60 ml/min.

4.4. Special warnings and precautions for use

Renal function

Deferasirox has been studied only in patients with baseline serum creatinine within the age-appropriate normal range.

During clinical studies, increases in serum creatinine of >33% on ≥2 consecutive occasions, sometimes above the upper limit of the normal range, occurred in about 36% of patients. These were dose-dependent. About two-thirds of the patients showing serum creatinine increase returned below the 33% level without dose adjustment. In the remaining third the serum creatinine increase did not always respond to a dose reduction or a dose interruption. In some cases, only a stabilisation of the serum creatinine values has been observed after dose reduction. Cases of acute renal failure have been reported following post-marketing use of deferasirox (see section 4.8). In some post-marketing cases, renal function deterioration has led to renal failure requiring temporary or permanent dialysis.

The causes of the rises in serum creatinine have not been elucidated. Particular attention should therefore be paid to monitoring of serum creatinine in patients who are concomitantly receiving medicinal products that depress renal function, and in patients who are receiving high doses of deferasirox and/or low rates of transfusion (<7 ml/kg/month of packed red blood cells or <2 units/month for an adult). While no increase in renal adverse events was observed after dose escalation of deferasirox dispersible tablets to doses above 30 mg/kg in clinical studies, an increased risk of renal adverse events with film-coated tablet doses above 21 mg/kg cannot be excluded.

It is recommended that serum creatinine be assessed in duplicate before initiating therapy. Serum creatinine, creatinine clearance (estimated with the Cockcroft-Gault or MDRD formula in adults and with the Schwartz formula in children) and/or plasma cystatin C levels should be monitored prior to therapy, weekly in the first month after initiation or modification of therapy with deferasirox (including switch of formulation), and monthly thereafter. Patients with pre-existing renal conditions and patients who are receiving medicinal products that depress renal function may be more at risk of complications. Care should be taken to maintain adequate hydration in patients who develop diarrhoea or vomiting.

There have been post-marketing reports of metabolic acidosis occurring during treatment with deferasirox. The majority of these patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhoea, or conditions where acid-base imbalance is a known complication. Acid-base balance should be monitored as clinically indicated in these populations. Interruption of deferasirox therapy should be considered in patients who develop metabolic acidosis.

Post-marketing cases of severe forms of renal tubulopathy (such as Fanconi syndrome) and renal failure associated with changes in consciousness in the context of hyperammonaemic encephalopathy have been reported in patients treated with deferasirox, mainly in children. It is recommended that hyperammonaemic encephalopathy be considered and ammonia levels measured in patients who develop unexplained changes in mental status while on Deferasirox Mylan therapy.

Table 3 Dose adjustment and interruption of treatment for renal monitoring

Serum creatinine

Creatinine clearance

Before initiation of therapy

Twice (2×)

and

Once (1×)

Contraindicated

<60 ml/min

Monitoring

First month after start of therapy or dose modification (including switch of formulation)

Weekly

and

Weekly

Thereafter

Monthly

and

Monthly

Reduction of daily dose by 7 mg/kg/day (film-coated tablet formulation),

if following renal parameters are observed at two consecutive visits and cannot be attributed to other causes

Adult patients

>33% above pre- treatment average

and

Decreases <LLN* (<90 ml/min)

Paediatric patients

> age appropriate ULN**

and/or

Decreases <LLN* (<90 ml/min)

After dose reduction, interrupt treatment, if

Adult and paediatric

Remains >33% above pre-treatment average

and/or

Decreases <LLN* (<90 ml/min)

* LLN: lower limit of the normal range

** ULN: upper limit of the normal range

Treatment may be reinitiated depending on the individual clinical circumstances

Dose reduction or interruption may be also considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated:

• Proteinuria (test should be performed prior to therapy and monthly thereafter)

• Glycosuria in non-diabetics and low levels of serum potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria (monitor as needed).

Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with Deferasirox Mylan.

Patients should be referred to a renal specialist, and further specialised investigations (such as renal biopsy) may be considered if the following occur despite dose reduction and interruption:

• Serum creatinine remains significantly elevated and

• Persistent abnormality in another marker of renal function (e.g. proteinuria, Fanconi Syndrome).

Hepatic function

Liver function test elevations have been observed in patients treated with deferasirox. Post-marketing cases of hepatic failure, sometimes fatal, have been reported in patients treated with deferasirox. Severe forms associated with changes in consciousness in the context of hyperammonaemic encephalopathy, may occur in patients treated with deferasirox, particularly in children. It is recommended that hyperammonaemic encephalopathy be considered and ammonia levels measured in patients who develop unexplained changes in mental status while on Deferasirox Mylan. Care should be taken to maintain adequate hydration in patients who experience volume-depleting events (such as diarrhoea or vomiting), particularly in children with acute illness. Most reports of hepatic failure involved patients with significant comorbidities including pre-existing chronic liver conditions (including cirrhosis and hepatitis C) and multi-organ failure. The role of deferasirox as a contributing or aggravating factor cannot be excluded (see section 4.8).

It is recommended that serum transaminases, bilirubin and alkaline phosphatase be checked before the initiation of treatment, every 2 weeks during the first month and monthly thereafter. If there is a persistent and progressive increase in serum transaminase levels that cannot be attributed to other causes, deferasirox should be interrupted. Once the cause of the liver function test abnormalities has been clarified or after return to normal levels, cautious re-initiation of treatment at a lower dose followed by gradual dose escalation may be considered.

Deferasirox Mylan is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) (see section 5.2).

Table 4 Summary of safety monitoring recommendations

Test

Frequency

Serum creatinine

In duplicate prior to therapy.

Weekly during first month of therapy or after dose modification (including switch of formulation).

Monthly thereafter.

Creatinine clearance and/or plasma cystatin C

Prior to therapy.

Weekly during first month of therapy or after dose modification (including switch of formulation).

Monthly thereafter.

Proteinuria

Prior to therapy.

Monthly thereafter.

Other markers of renal tubular function (such as glycosuria in non-diabetics and low levels of serum potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria)

As needed.

Serum transaminases, bilirubin, alkaline phosphatase

Prior to therapy.

Every 2 weeks during first month of therapy.

Monthly thereafter.

Auditory and ophthalmic testing

Prior to therapy.

Annually thereafter.

Body weight, height and sexual development

Prior to therapy.

Annually in paediatric patients.

In patients with a short life expectancy (e.g. high-risk myelodysplastic syndromes), especially when co-morbidities could increase the risk of adverse events, the benefit of Deferasirox Mylan might be limited and may be inferior to risks. As a consequence, treatment with Deferasirox Mylan is not recommended in these patients.

Caution should be used in elderly patients due to a higher frequency of adverse reactions (in particular, diarrhoea).

Data in children with non-transfusion-dependent thalassaemia are very limited (see section 5.1). As a consequence, Deferasirox Mylan therapy should be closely monitored to detect adverse reactions and to follow iron burden in the paediatric population. In addition, before treating heavily iron-overloaded children with non-transfusion-dependent thalassaemia with Deferasirox Mylan, the physician should be aware that the consequences of long-term exposure in such patients are currently not known.

Gastrointestinal disorders

Upper gastrointestinal ulceration and haemorrhage have been reported in patients, including children and adolescents, receiving deferasirox. Multiple ulcers have been observed in some patients (see section 4.8). There have been reports of ulcers complicated with digestive perforation. Also, there have been reports of fatal gastrointestinal haemorrhages, especially in elderly patients who had haematological malignancies and/or low platelet counts. Physicians and patients should remain alert for signs and symptoms of gastrointestinal ulceration and haemorrhage during Deferasirox Mylan therapy. In case of gastrointestinal ulceration or haemorrhage, Deferasirox Mylan should be discontinued and additional evaluation and treatment must be promptly initiated. Caution should be exercised in patients who are taking Deferasirox Mylan in combination with substances that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral bisphosphonates, in patients receiving anticoagulants and in patients with platelet counts below 50,000/mm³ (50 × 109/l) (see section 4.5).

Skin disorders

Skin rashes may appear during Deferasirox Mylan treatment. The rashes resolve spontaneously in most cases. When interruption of treatment may be necessary, treatment may be reintroduced after resolution of the rash, at a lower dose followed by gradual dose escalation. In severe cases, this reintroduction could be conducted in combination with a short period of oral steroid administration. Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life- threatening or fatal, have been reported. If any SCAR is suspected, Deferasirox Mylan should be discontinued immediately and should not be reintroduced. At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions, and be closely monitored.

Hypersensitivity reactions

Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving deferasirox, with the onset of the reaction occurring in the majority of cases within the first month of treatment (see section 4.8). If such reactions occur, Deferasirox Mylan should be discontinued and appropriate medical intervention instituted. Deferasirox should not be reintroduced in patients who have experienced a hypersensitivity reaction due to the risk of anaphylactic shock (see section 4.3).

Vision and hearing

Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported (see section 4.8). Auditory and ophthalmic testing (including fundoscopy) is recommended before the start of treatment and at regular intervals thereafter (every 12 months). If disturbances are noted during the treatment, dose reduction or interruption may be considered.

Blood disorders

There have been post-marketing reports of leukopenia, thrombocytopenia or pancytopenia (or aggravation of these cytopenias) and of aggravated anaemia in patients treated with deferasirox. Most of these patients had pre-existing haematological disorders that are frequently associated with bone marrow failure. However, a contributory or aggravating role cannot be excluded. Interruption of treatment should be considered in patients who develop unexplained cytopenia.

Other considerations

Monthly monitoring of serum ferritin is recommended in order to assess the patient's response to therapy and to avoid over-chelation (see section 4.2). Dose reduction or closer monitoring of renal and hepatic function, and serum ferritin levels are recommended during periods of treatment with high doses and when serum ferritin levels are close to the target range. If serum ferritin falls consistently below 500 µg/l (in transfusional iron overload) or below 300 µg/l (in non-transfusion-dependent thalassaemia syndromes), an interruption of treatment should be considered.

The results of the tests for serum creatinine, serum ferritin and serum transaminases should be recorded and regularly assessed for trends.

In two clinical studies, growth and sexual development of paediatric patients treated with deferasirox for up to 5 years were not affected (see section 4.8). However, as a general precautionary measure in the management of paediatric patients with transfusional iron overload, body weight, height and sexual development should be monitored prior to therapy and at regular intervals (every 12 months).

Cardiac dysfunction is a known complication of severe iron overload. Cardiac function should be monitored in patients with severe iron overload during long-term treatment with Deferasirox Mylan.

Sodium content

Deferasirox Mylan contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

The safety of deferasirox in combination with other iron chelators has not been established. Therefore, it must not be combined with other iron chelator therapies (see section 4.3).

Interaction with food

The Cmax of deferasirox film-coated tablets was increased (by 29%) when taken with a high-fat meal. Deferasirox Mylan film-coated tablets may be taken either on an empty stomach or with a light meal, preferably at the same time each day (see sections 4.2 and 5.2).

Agents that may decrease Deferasirox Mylan systemic exposure

Deferasirox metabolism depends on UGT enzymes. In a healthy volunteer study, the concomitant administration of deferasirox (single dose of 30 mg/kg, dispersible tablet formulation) and the potent UGT inducer, rifampicin, (repeated dose of 600 mg/day) resulted in a decrease of deferasirox exposure by 44% (90% CI: 37% – 51%). Therefore, the concomitant use of Deferasirox Mylan with potent UGT inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, ritonavir) may result in a decrease in Deferasirox Mylan efficacy. The patient's serum ferritin should be monitored during and after the combination, and the dose of Deferasirox Mylan adjusted if necessary.

Cholestyramine significantly reduced the deferasirox exposure in a mechanistic study to determine the degree of enterohepatic recycling (see section 5.2).

Interaction with midazolam and other agents metabolised by CYP3A4

In a healthy volunteer study, the concomitant administration of deferasirox dispersible tablets and midazolam (a CYP3A4 probe substrate) resulted in a decrease of midazolam exposure by 17% (90% CI: 8% – 26%). In the clinical setting, this effect may be more pronounced. Therefore, due to a possible decrease in efficacy, caution should be exercised when deferasirox is combined with substances metabolised through CYP3A4 (e.g. ciclosporin, simvastatin, hormonal contraceptive agents, bepridil, ergotamine).

Interaction with repaglinide and other agents metabolised by CYP2C8

In a healthy volunteer study, the concomitant administration of deferasirox as a moderate CYP2C8 inhibitor (30 mg/kg daily, dispersible tablet formulation), with repaglinide, a CYP2C8 substrate, given as a single dose of 0.5 mg, increased repaglinide AUC and Cmax about 2.3-fold (90% CI [2.03–2.63]) and 1.6-fold (90% CI [1.42–1.84]), respectively. Since the interaction has not been established with dosages higher than 0.5 mg for repaglinide, the concomitant use of deferasirox with repaglinide should be avoided. If the combination appears necessary, careful clinical and blood glucose monitoring should be performed (see section 4.4). An interaction between deferasirox and other CYP2C8 substrates like paclitaxel cannot be excluded.

Interaction with theophylline and other agents metabolised by CYP1A2

In a healthy volunteer study, the concomitant administration of deferasirox as a CYP1A2 inhibitor (repeated dose of 30 mg/kg/day, dispersible tablet formulation) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an increase of theophylline AUC by 84% (90% CI: 73% to 95%). The single dose Cmax was not affected, but an increase of theophylline Cmax is expected to occur with chronic dosing. Therefore, the concomitant use of deferasirox with theophylline is not recommended. If deferasirox and theophylline are used concomitantly, monitoring of theophylline concentration and theophylline dose reduction should be considered. An interaction between deferasirox and other CYP1A2 substrates cannot be excluded. For substances that are predominantly metabolised by CYP1A2 and that have a narrow therapeutic index (e.g. clozapine, tizanidine), the same recommendations apply as for theophylline.

Other information

The concomitant administration of deferasirox and aluminium-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminium than for iron, it is not recommended to take deferasirox tablets with aluminium-containing antacid preparations.

The concomitant administration of deferasirox with substances that have known ulcerogenic potential, such as NSAIDs (including acetylsalicylic acid at high dosage), corticosteroids or oral bisphosphonates may increase the risk of gastrointestinal toxicity (see section 4.4). The concomitant administration of deferasirox with anticoagulants may also increase the risk of gastrointestinal haemorrhage. Close clinical monitoring is required when deferasirox is combined with these substances.

Concomitant administration of deferasirox and busulfan resulted in an increase of busulfan exposure (AUC), but the mechanism of the interaction remains unclear. If possible, evaluation of the pharmacokinetics (AUC, clearance) of a busulfan test dose should be performed to allow dose adjustment.

4.6. Fertility, pregnancy and lactation

Pregnancy

No clinical data on exposed pregnancies are available for deferasirox. Studies in animals have shown some reproductive toxicity at maternally toxic doses (see section 5.3). The potential risk for humans is unknown.

As a precaution, it is recommended that Deferasirox Mylan is not used during pregnancy unless clearly necessary.

Deferasirox Mylan may decrease the efficacy of hormonal contraceptives (see section 4.5). Women of childbearing potential are recommended to use additional or alternative non-hormonal methods of contraception when using Deferasirox Mylan.

Breast-feeding

In animal studies, deferasirox was found to be rapidly and extensively secreted into maternal milk. No effect on the offspring was noted. It is not known if deferasirox is secreted into human milk.

Breast-feeding while taking Deferasirox Mylan is not recommended.

Fertility

No fertility data is available for humans. In animals, no adverse effects on male or female fertility were found (see section 5.3).

4.7. Effects on ability to drive and use machines

Deferasirox Mylan has minor influence on the ability to drive and use machines. Patients experiencing the uncommon adverse reaction of dizziness should exercise caution when driving or operating machines (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The most frequent reactions reported during chronic treatment in clinical studies conducted with deferasirox dispersible tablets in adult and paediatric patients include gastrointestinal disturbances (mainly nausea, vomiting, diarrhoea or abdominal pain) and skin rash. Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years and in the elderly. These reactions are dose-dependent, mostly mild to moderate, generally transient and mostly resolve even if treatment is continued.

During clinical studies dose-dependent increases in serum creatinine occurred in about 36% of patients, though most remained within the normal range. Decreases in mean creatinine clearance have been observed in both paediatric and adult patients with beta-thalassemia and iron overload during the first year of treatment, but there is evidence that this does not decrease further in subsequent years of treatment. Elevations of liver transaminases have been reported. Safety monitoring schedules for renal and liver parameters are recommended. Auditory (decreased hearing) and ocular (lens opacities) disturbances are uncommon, and yearly examinations are also recommended (see section 4.4).

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with the use of Deferasirox Mylan (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions are ranked below using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 5

Blood and lymphatic system disorders

Not known:

Pancytopenia1, thrombocytopenia1, anaemia aggravated1, neutropenia1

Immune system disorders

Not known:

Hypersensitivity reactions (including anaphylactic reactions and angioedema)1

Metabolism and nutrition disorders

Not known:

Metabolic acidosis1

Psychiatric disorders

Uncommon:

Anxiety, sleep disorder

Nervous system disorders

Common:

Headache

Uncommon:

Dizziness

Eye disorders

Uncommon:

Cataract, maculopathy

Rare:

Optic neuritis

Ear and labyrinth disorders

Uncommon:

Deafness

Respiratory, thoracic and mediastinal disorders

Uncommon:

Laryngeal pain

Gastrointestinal disorders

Common:

Diarrhoea, constipation, vomiting, nausea, abdominal pain, abdominal distension, dyspepsia

Uncommon:

Gastrointestinal haemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, gastritis

Rare:

Oesophagitis

Not known:

Gastrointestinal perforation1, acute pancreatitis1

Hepatobiliary disorders

Common:

Transaminases increased

Uncommon:

Hepatitis, cholelithiasis

Not known:

Hepatic failure1,2

Skin and subcutaneous tissue disorders

Common:

Rash, pruritus

Uncommon:

Pigmentation disorder

Rare:

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Not known:

Stevens-Johnson syndrome1, hypersensitivity vasculitis1, urticaria1, erythema multiforme1, alopecia1, toxic epidermal necrolysis (TEN)1

Renal and urinary disorders

Very common:

Blood creatinine increased

Common:

Proteinuria

Uncommon:

Renal tubular disorder2 (acquired Fanconi syndrome), glycosuria

Not known:

Acute renal failure1,2, tubulointerstitial nephritis1, nephrolithiasis1, renal tubular necrosis1

General disorders and administration site conditions

Uncommon:

Pyrexia, oedema, fatigue

1 Adverse reactions reported during post-marketing experience. These are derived from spontaneous reports for which it is not always possible to reliably establish frequency or a causal relationship to exposure to the medicinal product.

2 Severe forms associated with changes in consciousness in the context of hyperammonaemic encephalopathy have been reported.

Description of selected adverse reactions

Gallstones and related biliary disorders were reported in about 2% of patients. Elevations of liver transaminases were reported as an adverse reaction in 2% of patients. Elevations of transaminases greater than 10 times the upper limit of the normal range, suggestive of hepatitis, were uncommon (0.3%). During post-marketing experience, hepatic failure, sometimes fatal, has been reported with deferasirox (see section 4.4). There have been post-marketing reports of metabolic acidosis. The majority of these patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhoea, or conditions where acid-base imbalance is a known complication (see section 4.4). Cases of serious acute pancreatitis were observed without documented underlying biliary conditions. As with other iron chelator treatment, high-frequency hearing loss and lenticular opacities (early cataracts) have been uncommonly observed in patients treated with deferasirox (see section 4.4).

Creatinine clearance in transfusional iron overload

In a retrospective meta-analysis of 2,102 adult and paediatric beta-thalassaemia patients with transfusional iron overload treated with deferasirox dispersible tablets in two randomised and four open label studies of up to five years' duration, a mean creatinine clearance decrease of 13.2% in adult patients (95% CI: −14.4% to −12.1%; n=935) and 9.9% (95% CI:−11.1% to −8.6%; n=1,142) in paediatric patients was observed during the first year of treatment. In 250 patients who were followed for up to five years, no further decrease in mean creatinine clearance levels was observed.

Clinical study in patients with non-transfusion-dependent thalassaemia syndromes

In a 1-year study in patients with non-transfusion-dependent thalassaemia syndromes and iron overload (dispersible tablets at a dose of 10 mg/kg/day), diarrhoea (9.1%), rash (9.1%), and nausea (7.3%) were the most frequent study drug-related adverse events. Abnormal serum creatinine and creatinine clearance values were reported in 5.5% and 1.8% of patients, respectively. Elevations of liver transaminases greater than 2 times the baseline and 5 times the upper limit of normal were reported in 1.8% of patients.

Paediatric population

In two clinical studies, growth and sexual development of paediatric patients treated with deferasirox for up to 5 years were not affected (see section 4.4).

Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years than in older patients.

Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with deferasirox. In post-marketing reports, a high proportion of cases of metabolic acidosis occurred in children in the context of Fanconi syndrome.

Acute pancreatitis has been reported, particularly in children and adolescents.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Early signs of acute overdose are digestive effects such as abdominal pain, diarrhoea, nausea and vomiting. Hepatic and renal disorders have been reported, including cases of liver enzyme and creatinine increased with recovery after treatment discontinuation. An erroneously administered single dose of 90 mg/kg led to Fanconi syndrome which resolved after treatment.

There is no specific antidote for deferasirox. Standard procedures for management of overdose may be indicated as well as symptomatic treatment, as medically appropriate.